Peripheral & Brain Cholesterol Metabolism in Neurodegenerative Mouse Models

描述(申请人提供)：散发性阿尔茨海默病(AD)是一种病因不明的晚发性痴呆，其特征是淀粉样蛋白(Aβ，Aβ)的存在，其中包含老年斑、神经原纤维缠结和认知能力下降。重要的是，载脂蛋白(ApoE)等位基因的遗传是唯一已确定的散发性晚发性AD的危险因素。然而，这种联系背后的机制仍然难以捉摸。三磷酸腺苷结合盒转运体A1(ABCA1)调节胆固醇从细胞到胆固醇受体的外流，主要是低脂载脂蛋白A-I(apoA-I)和载脂蛋白E，从而产生新生高密度脂蛋白(HDL)。在表达APP的小鼠中，ABCA1的中断增加了脑实质中的斑块水平和脑淀粉样血管病变。值得注意的是，伴随着脑脊液中高密度脂蛋白样颗粒结构的异常以及载脂蛋白A-I和载脂蛋白E水平的降低。因此，调节载脂蛋白E表达和脂化的过程可能会影响其影响脑Aβ动态平衡的能力。支持这一假设的是，携带者的载脂蛋白E水平较低与A、β病理和AD风险增加相关。此外，在AD小鼠模型中，LXR和RXR激动剂刺激APOE表达和脂化与减少病理和改善认知有关。中心假说是ABCA1通过脂化载脂蛋白E和高密度脂蛋白的形成影响Aβ的形成/沉积和清除，因此影响ABCA1和ApoE水平的治疗方法可用于治疗Aβ的病理。为了证明这一假设，我们使用病毒载体过表达载脂蛋白和多光子显微镜在体内评估了对APP转基因小鼠Aβ病理和神经元异常的影响。此外，我们将表征ABCA1的一个临床显著突变对APP小鼠模型表型的影响。最后，我们将研究ABCA1外周和中枢表达的变化如何影响脂类和淀粉样蛋白水平。这项应用的完成将对我们理解不同的APOE等位基因和ABCA1的临床相关突变如何影响淀粉样蛋白病理产生重大影响。该设计将使我们能够更深入地了解APOE影响AD进展的可能机制。此外，这项应用将进一步加深我们对中枢和外周ABCA1在大脑脂质谱和淀粉样蛋白水平中的重要性的理解，从而改善治疗目标。

DESCRIPTION (provided by applicant): Sporadic Alzheimer's disease (AD) is a late-onset dementia of unknown etiology, characterized by the presence of amyloid β (Aβ) containing senile plaques, neurofibrillary tangles, and cognitive decline. Importantly, the inheritance of Apolipoprotein (APOE) allele is the only established risk factor for sporadic late onset AD. However, the mechanism underlying this association remains elusive. ATP binding cassette transporter A1 (ABCA1) regulates cholesterol efflux from cells to cholesterol acceptors, primarily poorly lipidated apolipoprotein A-I (APOA-I) and APOE thus generating nascent high density lipoprotein (HDL). Disruption of Abca1 in APP expressing mice increased plaque levels in brain parenchyma and cerebral amyloid angiopathy. Remarkably this was accompanied by abnormal HDL-like particle structure in the CSF and decreased levels of APOA-I and APOE. Thus, processes that regulate APOE expression and lipidation could affect its ability to influence brain Aβ homeostasis. In support of this hypothesis the lower level of APOE in carriers is associated with increased Aβ pathology and AD risk. Furthermore, stimulation of APOE expression and lipidation with LXR and RXR agonists is associated with reduced pathology and improved cognition in AD mouse models. The central hypothesis is that Abca1 affects Aβ formation/deposition and clearance, through lipidation of ApoE and formation of HDL, therefore therapeutic approaches which affect the levels of Abca1 and ApoE can be used to treat the Aβ pathology. To prove the hypothesis we use viral vectors to overexpress apolipoproteins and multiphoton microscopy to assess in vivo the effects on Aβ pathology and neuronal abnormalities in APP transgenic mice. Furthermore, we will characterize the effects of a clinically significant mutation of ABCA1 on APP mouse model phenotype. Lastly, we will examine how changes in peripheral and central expression of Abca1 affect lipid profiles and amyloid levels. The completion of this application will have a significant impact on our understanding of how different APOE alleles and a clinical relevant mutation of ABCA1 effects amyloid pathology. The design will allow for much more insight into a possible mechanism by which APOE affects AD progression. Furthermore, the application will further our understanding of the importance of central and peripheral ABCA1 in brain lipid profiles and amyloid levels, allowing for improved treatment targets.